tbuckley/cabot-search huggingface dataset:
Pembrolizumab (pembro) monotherapy for patients (pts) with high-risk non–muscle-invasive bladder cancer (HR NMIBC) unresponsive to bacillus Calmette–Guérin (BCG): Results from cohort B of the phase 2 KEYNOTE-057 trial.
Authors: Andrea Necchi, Mathieu Roumiguié, Ahmet Adil Esen, Thierry Lebret, Ronald De Wit, Neal D. Shore, Dean F. Bajorin, Laurence E. M. Krieger, Shuya Kandori, Edward M. Uchio, Ho Kyung Seo, Joost Boormans, Ashish M. Kamat, Eric A. Singer, Petros Grivas, Hiroyuki Nishiyama, Kijoeng Nam, Ekta Kapadia, Margot Van den Sigtenhorst-Fijlstra, Girish S. Kulkarni
Journal: Journal of Clinical Oncology (2023)

LBA442 Background: Although most pts with HR NMIBC respond to BCG, pts whose cancer does not respond or who relapse within 12 mo have poor prognosis and require radical cystectomy (RC). The single-arm, multicohort phase 2 KEYNOTE-057 trial (NCT02625961) was designed to investigate the safety and efficacy of pembro monotherapy for pts with BCG-unresponsive HR NMIBC (per FDA) who were ineligible or declined to undergo RC. Results from cohort A (carcinoma in situ [CIS] ± papillary tumors) showed a clinical complete response rate of 41% at 3 mo and led to approval of pembro monotherapy for such pts in the United States. We describe the results from cohort B (papillary tumors without CIS). Methods: Pts were aged ≥18 y with BCG-unresponsive HR NMIBC with papillary tumors only (high-grade Ta or any-grade T1) at baseline and ECOG PS 0-2. Pts received pembro 200 mg every 3 wk (Q3W) for ≤35 cycles (~2 y). Cancer was assessed at 12 wk and Q12W thereafter if no recurrent HR NMIBC or progression was observed; CT urography was done Q24W. Primary end points for cohort B were 12-mo disease-free survival (DFS) rate of HR NMIBC as assessed by central pathology/radiology review and safety, assuming a 12-mo DFS of &gt;20% for HR NMIBC. Secondary efficacy end points were 12-mo DFS rate of any disease; progression-free survival (PFS) to worsening of grade, stage, or death; PFS to muscle invasion, metastasis, or death; and overall survival (OS). Results: Overall, 132 pts received pembro for a median of 9.5 cycles (range, 1.0-35.0). Median age was 72 y (range, 37-87); 57 pts (43.2%) had T1 stage; all pts (100%) had urothelial histology; 104 pts (78.8%) were male; pts received a median of 10 (range, 6-33) prior BCG instillations. Median follow-up was 45.4 mo (range, 14.9-77.1). Efficacy data are shown in Table. Thirty-one pts (23.5%) had RC after stopping pembro. Treatment-related AEs occurred in 97 pts (73.5%); 19 (14.4%) had a grade 3/4 treatment-related AE and 14 pts (10.6%) discontinued due to a treatment-related AE. No deaths from treatment-related AEs occurred. Conclusions: Pembro showed notable antitumor activity in pts with BCG-unresponsive non-CIS papillary HR NMIBC after ~45 mo of follow-up. Toxicity was manageable and consistent with that in cohort A, with no new safety signals. Results suggest pts with non-CIS papillary HR NMIBC unresponsive to BCG who declined or were ineligible to undergo RC may also benefit from pembro monotherapy. Clinical trial information: NCT02625961 . [Table: see text]
A phase 2 randomized open-label study of oral darolutamide monotherapy vs. androgen deprivation therapy in men with hormone-naive prostate cancer (EORTC-GUCG 1532).
Authors: Bertrand F. Tombal, Francisco Gomez-Veiga, Alvaro Gomez-Ferrer, Fernando López-Campos, Piet Ost, Thierry Andre Roumeguere, Bernardo Herrera-Imbroda, Lionel A. D'Hondt, Magali Quivrin, Paolo Gontero, Salvador Villà, Hussein Mustafa Khaled, Beatrice Fournier, Joanna Krzystyniak, Yassin Pretzenbacher, Hazal Erkol, Yohann Loriot
Journal: Journal of Clinical Oncology (2023)

160 Background: Darolutamide is androgen-receptor (AR) inhibitor with low blood–brain barrier penetration and limited potential for clinically relevant drug–drug interactions. Darolutamide has been shown to increase overall survival in combination with androgen deprivation therapy (ADT) in patients with newly diagnosed metastatic hormone sensitive prostate cancer (PC) and, in combination with docetaxel, in men with non-metastatic castration resistant PC. This phase 2 study assessed the efficacy and safety of DARO as a monotherapy without ADT in patients with non-castrate testosterone (T) levels (≥230 ng/dL). Methods: This was a 24-wk, open-label, randomized study of patients with hormone-naïve, histologically confirmed prostate cancer (all stages, with a max of 4 metastatic lesions) requiring hormonal treatment, an ECOG PS score of 0, and a life expectancy &gt;1 y. All patients received DARO 600 mg bid or commercially available LHRH analogue. The primary endpoint is PSA response defined as a ≥ 80% decline at week 24 relative to baseline, in the DARO study arm. The ADT arm is used as an internal control. Secondary endpoints included changes in T levels, safety/tolerability, and quality of life. Results: Among 61 men enrolled, the median (range) age was 72 y (53-86y); 49.2% had metastases; 14.8% and 62.3% had undergone prostatectomy or radiotherapy before study entry. The median (range) of PSA at baseline was 8.9 ng/mL (2.2-333.8). In the DARO arm, the evaluable population with available PSA values at baseline and week 24 consisted of 21 patients. The PSA response rate (&gt;80% PSA decline at wk 24) was 100%, with a median (range) decrease of -99.6% (-94.3, -100) at wk 24 in the DARO arm. Serum T levels increased by a median (range) of 43.4% (5.7-144.0) at wk 24, compared with baseline. In the DARO arm, 45.2% of men reported drug-related AEs (mostly Grade 1 or 2). Most frequent treatment-emergent AEs included gynaecomastia (19.4%), fatigue (12.9%), and hot flush (12.9%). 3.1% of men experienced SAEs, none of which were drug related. HR-QoL measures and ADT arm results will be presented as internal reference. Conclusions: DARO monotherapy (600 mg bid) was associated with significant PSA response in nearly all men with hormone-naïve prostate cancer. Testosterone level changes and most common AEs (gynecomastica, fatigue and hot flush) were consistent with potent AR inhibition. Clinical trial information: NCT02972060 .
Updated results of a phase Ib single-center study of pembrolizumab in combination with chemotherapy in patients with locally advanced or metastatic small cell/neuroendocrine cancers of the prostate and urothelium.
Authors: Arnold I. Chin, Ann Ly, Sara Rodriguez, Ankush Sachdeva, Nazy Zomorodian, Hanwei Zhang, Jiyoon Kim, Gang Li, Matthew Rettig, Sandy Liu, Alexandra Drakaki
Journal: Journal of Clinical Oncology (2023)

165 Background: Small cell/neuroendocrine cancers irrespective of origin share aggressive phenotypes. Pembrolizumab (MK-3475) is a humanized antibody targeting programmed cell death protein 1 (PD-1) that has shown activity against small cell lung cancers. Preclinical studies showed molecular commonality amongst small cell cancers across multiple tissue types. This study evaluated the safety and efficacy signals of pembrolizumab and chemotherapy in patients with small cell/neuroendocrine cancer of the prostate and urothelium. Methods: Patients with locally advanced or metastatic small cell cancer of the bladder (cohort 1) and primary small cell or treatment-derived neuroendocrine prostate cancer (NEPC) (cohort 2) received pembrolizumab and standard of care chemotherapy (etoposide and cisplatin/carboplatin for cohorts 1 and 2, with option of docetaxel and carboplatin for cohort 2) with maintenance pembrolizumab for 2 years until unequivocal progressive disease or unacceptable toxicity. Primary endpoint was to estimate ORR, PFS, and OS compared to historical controls as well as safety and tolerability. Targeted gene mutation sequencing as well as sequential single cell sequencing of peripheral blood mononuclear cells (PBMCs) for immune profiling as well T cell receptor (TCR) repertoire was performed. Results: 14 patients were enrolled (7 cohort 1, 7 cohort 2) with mean age 64.9 (range 53 to 81). ORR was 43% (95% CI: 0.06, 0.80) overall and within each cohort. PFS rate at 12 months was 64% (95% CI: 0.44,0.95) across cohorts, 86% (95% CI: 0.63,1.00) within cohort 1, and 43% (95% CI: 0.18,1.00) within cohort 2. OS rate at 12 months was 79% (95% CI: 0.60,1.00) across cohorts, 86% (95% CI: 0.63,1.00) within cohort 1, and 71% (95% CI: 0.45,1.00) within cohort 2. 4 patients in cohort 1 with locally advanced disease underwent radical cystectomy, with no PD at a mean follow up of 29 months. Grade 3 or higher AEs occurred in 87% of patients, while 40% of patients experienced grade 3 or higher AEs related to pembrolizumab. In 12 patients where tissue was sufficient, all patients had genomic alterations in either p53 (75%) or Rb (58%). Single cell sequencing showed progressive enrichment of CD8 + T cells with clonal expansion of specific TCRs in responding patients. Conclusions: In patients with locally advanced or metastatic small cell/neuroendocrine prostate and bladder cancers, combination pembrolizumab with standard of care chemotherapy and maintenance pembrolizumab showed promising efficacy with tolerable adverse events. Clinical trial information: NCT03582475 .
A phase II trial of combination of PD-1 immune checkpoint inhibition with all-lesion stereotactic radiation (SBRT) in oligometastatic renal cell carcinoma (omRCC).
Authors: Jing Liu, Benkui Zou, Chao Zhang, Kunli Zhu, Rui Feng, Lei Xu, Xue Dou, Pengyue Shi, Yun Zhang, Jinbo Yue
Journal: Journal of Clinical Oncology (2023)

677 Background: Although systemic therapy has recently made strides, the 5-year survival rate of mRCC patients is still low — around 10%. Through the abscopal effect, SBRT can improve the antitumor immunity of PD-1 immune checkpoint inhibition (ICI) in metastatic RCC. OmRCC patients have a low tumor load and a favorable prognosis, so more active treatment strategies are needed. It might work even better when all lesions of omRCC are controlled by SBRT. The study aims to evaluate whether the antitumour immunity can be enhanced by combination of ICI and all-lesion SBRT for omRCC. Methods: Patients with progression disease after ≤ 2 prior anti-angiogenic therapies and with ≤ 5 lesions located in ≤ 3 non-brain metastatic sites may all suitable for SBRT are included. Tislelizumab was given as 200 mg in intravenously on day 1, Q3W, until PD or unacceptable toxicity. Hypofractionated radiation at a dose and schedule of 5-8 Gy×3-10 fractions were performed according to lesion site, size and organs at risk individually. SBRT of first lesion were applied after 7 days from the first infusion of Tislelizumab. SBRT of other lesions were performed sequentially during the intervals of Tislelizumab. The primary objective is Objective Response Rate (ORR) according to RECIST v1.1. Secondary endpoints are progression free survival (PFS), overall survival (OS) and safety profile. An exploratory project also identifies molecular basis of synergistic effect of SBRT and immunotherapy, potential mechanisms of ICI resistance. Results: Fifteen patients were enrolled from May 2021 to May 2022. Totally 36 lesions were radiated, including 10 lung lesions (63 Gy/9 fractions), 10 bone lesions (24-40 Gy/5-8 fractions), 7 lymph nodes (30-50 Gy/6-10 fractions), 4 kidney lesions (40 Gy/5 fractions), and 5 other lesions. ORR were 33.3% for patients (CR=0, PR=5, SD=7, PD=2, not evaluable=1) and 27.8% for lesions (CR=2, PR=8, SD=11, PD=3, not evaluable=12). The most common treatment-related toxicities include fatigue (20%), hypothyroidism (20%), and pneumonia (13.3%), all with G1-2. One patient suffered G3 treatment-related hematologic toxicity. There were no treatment related deaths. Median PFS and OS were not reached. Conclusions: The combination of all-lesion SBRT with ICI is feasible and associated with an accepted safety profile. Encouraging antitumor activity was observed warranting further investigations. Clinical trial information: ChiECRCT20210046 .
Preclinical evaluation of teleglenastat (CB-839) in prostate cancer.
Authors: Elaine T. Lam, Lih-Jen Su, Maren Salzmann-Sullivan, Steven K. Nordeen, Thomas W. Flaig
Journal: Journal of Clinical Oncology (2023)

378 Background: Glutaminase (GLS) levels are upregulated in prostate cancer [PMID: 28138303, 16897757]. The androgen receptor signaling pathway enhances the expression of SLC43A1, SLC1A4 and SLC1A5 (amino acid and glutamine transporters) in prostate cancer cells [PMID: 22007000, 24052624, 28507054]. We evaluated prostate cancer data from The Cancer Genome Atlas and found that GLS expression correlates with Gleason sum. We performed in vitro and in vivo experiments to evaluate the effect CB-839, a glutaminase inhibitor (GLS1 &gt; GLS2), as monotherapy and in combination with other agents. Methods: We evaluated glutamine dependence of 3 prostate cancer cell lines [parental LNCaP (P0, hormone-sensitive), LNCaP-derived castrate resistant (CRPC) variant (P1, PMID: 34575033), and PC-3 (CRPC)] using media with and without glutamine, as well as clonogenic assays in regular media with BPTES (GLS1 inhibitor as a control) and CB-839. Combinatorial treatment and dose response studies were performed with CB-839 plus enzalutamide (ENZ), everolimus (EVE), or olaparib (OLA). We used NOD SCID female nude mice carrying P1 and PC3 prostate tumor xenografts to evaluate effects of CB-839 monotherapy, CB-839 + EVE, and EVE monotherapy. Results: P0, P1, and PC-3 all exhibited glutamine dependence. In glutamine-deplete media, all tested cell lines formed &lt; 50% of colonies from baseline. Clonogenic assays with BPTES showed IC50 of 2-6 uM. CB-839 showed single agent activity in vitro with IC50 = 1 uM (P0), IC50 = 2 (P1), and IC50 &lt; 0.1 uM (PC-3). The IC50 of CB-839 + ENZ in P1 cells was &lt; 4uM CB-839 + 2uM ENZ. CB-839 + OLA showed no additive effect as OLA alone was very active (IC50 &lt; 100 nM) in P1 cells. CB-839 + EVE showed single agent and synergistic effect (IC50 &lt; 4 uM CB-839 + 0.05 uM EVE) in both P1 and PC-3 cells. In P1 tumor xenografts, treatment response was seen in CB-839 monotherapy, EVE monotherapy, and CB-839 + EVE treatment arms. In PC-3 xenografts, treatment response was seen in all groups, with greater effect in the EVE monotherapy and CB-839 + EVE treatment groups compared with CB-839 monotherapy. Conclusions: CB-839, EVE, and CB-839 + EVE all demonstrated activity in P1 and PC-3 castrate resistant prostate cancer tumor xenografts. Additive or synergistic activity was difficult to assess with combination therapy since each drug was effective as monotherapy. Additional studies are needed to evaluate the role of EVE monotherapy or CB-839 + EVE in prostate cancer. Research Sponsors: NCI CTEP UM1 Supplement CA186688-04, NCI University of Colorado Cancer Center Support Grant 5P30CA046934-30. [Table: see text]
Phase Ib trial of enzalutamide (Enza) with venetoclax (Ven) in metastatic castration-resistant prostate cancer (mCRPC).
Authors: Stuthi Perimbeti, Anmbreen Jamroze, Kristopher Attwood, Bailey Farmer, Jan Hendrik Beumer, Robert Bies, Ellis Glenn Levine, Jason Kirk, Dean Tang, Gurkamal S. Chatta, Dharmesh Gopalakrishnan
Journal: Journal of Clinical Oncology (2023)

182 Background: Androgen receptor (AR) signaling is critical to prostate cancer (PCa) cell survival and proliferation. Androgen ablation leads to expansion of both AR −/lo and AR +/hi resistant clones in CRPC xenografts. Most current therapies for mCRPC are directed towards AR +/hi cells. BCL-2 is highly up-regulated in CRPC xenografts and human tumors post-Enza. Ven, a selective BCL-2 inhibitor, inhibits Enza resistance in AR −/lo and CRPC models. We hypothesize that co-targeting AR −/lo and AR +/hi clones with Ven and Enza may inhibit Enza resistance in human mCRPC. Methods: This is a phase 1b single center, single arm trial of fixed dose Enza (160mg/d) with escalating doses of Ven in patients with mCRPC that has progressed on multiple lines of prior therapies including antiandrogens to evaluate pharmacokinetics, safety and recommended phase 2 dose. A total of 10 patients were enrolled in the study. Three dose levels of Ven (400mg (DL1), 600mg (DL2), and 800mg (DL3)/d q28d) were evaluated using a 3+3 study design. Kaplan Meier method was used to estimate median overall survival (OS) and time to next systemic therapy (TNST). Results: Median age was 71.3 years and mean duration on treatment was 28.7 weeks (range: 8-140 weeks). On an average, each patient received 3 lines of treatment prior to enrollment(range:1-8). The most frequent treatment related adverse events (TRAEs) (&gt;10%) were mostly grade 1-2 as listed. Grade 3 TRAEs included hypertension (20%), fatigue (10%), and thrombocytopenia (10%). Grade 3 fatigue as DLT was reported in one patient in DL3. Only 1/10 (10%) attained PSA50 response; 4/10 (40%) patients had stable disease and 6/10 (60%) had disease progression as their best radiographic response. Median OS for the study population was 18.8 months (95% CI 5.3-28.2 months) and median TNST was 5.4 months (95% CI 0.9-34.6 months). Conclusions: This phase 1b trial demonstrates an acceptable toxicity profile for the combination of Enza and Ven in refractory mCRPC. PK evaluations and correlative biomarker studies are currently ongoing. Clinical trial information: NCT03751436 . [Table: see text]
Comparative transcriptomic analysis of DNA-damage response and androgen receptor pathway activity between biopsy and radical prostatectomy specimens before and after pre-operative real-time MRI-guided stereotactic body radiotherapy.
Authors: Himanshu Nagar, Alicia Dillard, Alexander K. Hakansson, Yang Liu, Elai Davicioni, Sydney Wolfe, Jim C. Hu, Douglas Scherr, Francesca Khani, Ariel E. E. Marciscano, Christopher Barbieri
Journal: Journal of Clinical Oncology (2023)

375 Background: Pre-Prostatectomy MRI-Guided Stereotactic Body Radiotherapy for High-Risk Prostate Cancer Trial (PREPARE SBRT; NCT03663218) is an ongoing clinical trial testing the safety of preoperative MRI-guided SBRT for men with clinically localized high-risk prostate cancer. We sought to compare transcriptomic profiles of biopsy (Bx) specimens to acutely irradiated radical prostatectomy (RP) specimens. Methods: Biopsy and post-irradiated RP specimens from 10 subjects were examined. The median interval between the end of RT and the date of RP was 5 days. Transcriptomic profiles were generated using Decipher GRID (Veracyte, Inc). Differences in transcriptional signatures were assessed between Bx samples taken before irradiation and RP samples post-irradiation using a paired T-Test. A control cohort of transcriptomic profiles of 803 untreated Bx samples and matching RP samples from the same patients were used to account for effects in tissue preservation from the procedure different of Bx vs RP. Linear regression model with the interaction effect of cohort (SBRT vs control) by procedure (Bx vs RP) to select signatures impacted by radiation treatment. Results: Transcriptomic signatures associated with Androgen Receptor (AR) activity were significantly downregulated (p=0.002) in irradiated RP specimens compared with pre-treatment biopsies. Analysis of DNA damage repair (DDR) pathways demonstrated that nucleotide excision repair (NER) and non-homologous end joining (NHEJ) signatures were increased (p=0.002 and p=0.02, respectively) after pre-operative RT whereas homologous recombination (p=0.06) and mismatch repair (p=0.08) were not significantly different between pre-treatment and irradiated tissues. Several metabolic-associated pathways were impacted by pre-operative RT including increased glycogen metabolism (p=0.008) and a NADH-NADPH conversion (p=0.001) signature indicative of RT-induced oxidative damage. Consistent upregulation of transcriptomic features associated with increased angiogenesis (p=0.0012) and stromal remodeling (p=0.0008) was observed in irradiated samples. Conclusions: Paired transcriptomic analysis following pre-operative RT demonstrated differential upregulation of specific DDR pathways including NHEJ and NER and metabolic alterations related to oxidative stress and glycogen metabolism. AR activity signatures were decreased in response to pre-operative RT.
Extended follow-up results from the CheckMate 274 trial.
Authors: Matt D. Galsky, Alfred Alfred Witjes, Jürgen E. Gschwend, Michael Schenker, Begoña Pérez Valderrama, Yoshihiko Tomita, Aristotelis Bamias, Thierry Lebret, Shahrokh F. Shariat, Se Hoon Park, Mads Agerbaek, Gautam Gopalji Jha, Frank Stenner, Santanu Dutta, Federico Nasroulah, Joshua Zhang, Lynne Brophy, Dean F. Bajorin
Journal: Journal of Clinical Oncology (2023)

LBA443 Background: The 2 primary endpoints of the CheckMate 274 trial were met as nivolumab (NIVO) improved disease-free survival (DFS) versus placebo (PBO) in the intent-to-treat (ITT) population and in patients with tumor programmed death ligand 1 (PD-L1) expression ≥ 1%. We report extended follow-up data. Methods: CheckMate 274 is a phase 3, double-blind trial of adjuvant NIVO versus PBO for high-risk muscle-invasive urothelial carcinoma (MIUC) (bladder, ureter, or renal pelvis) after radical resection. Patients were randomly assigned 1:1 to NIVO 240 mg every 2 wk or PBO for ≤ 1 year of treatment. Patients had pathologic evidence of UC at high risk of recurrence and Eastern Cooperative Oncology Group performance status (ECOG PS) ≤ 1. Primary endpoints were DFS in ITT patients and in patients with PD-L1 ≥ 1%. DFS was also analyzed in prespecified subgroups. Overall survival and non–urothelial tract recurrence-free survival (NUTRFS) in ITT patients and in patients with PD-L1 ≥ 1% were secondary endpoints. Distant metastasis-free survival (DMFS) and safety were exploratory endpoints. Results: There were 353 patients randomly assigned to NIVO (PD-L1 ≥ 1%, n = 140) and 356 to PBO (PD-L1 ≥ 1%, n = 142). With median follow-up of 36.1 months (minimum follow-up, 31.6 months), median DFS was 22.0 months with NIVO versus 10.9 months with PBO in ITT patients and 52.6 months with NIVO versus 8.4 months with PBO in patients with PD-L1 ≥ 1% (Table). DFS benefit was seen in most subgroups analyzed including age, sex, ECOG PS, nodal status, prior cisplatin-based chemotherapy, and PD-L1 status. NUTRFS and DMFS benefits with NIVO versus PBO were also observed in both populations (Table). Grade 3–4 treatment-related adverse events occurred in 18.2% and 7.2% of patients in the NIVO and PBO arms, consistent with the primary analysis. Overall survival will be assessed at a future database lock. Conclusions: With extended follow-up, NIVO continued to show DFS, NUTRFS, and DMFS benefits versus PBO. The hazard ratio (HR) for DFS and NUTRFS in PD-L1 ≥ 1% patients and for DMFS in both ITT and PD-L1 ≥ 1% patients also continued to improve versus the primary analysis. No new safety signals were identified. These results further support adjuvant NIVO as a standard of care for high-risk MIUC after radical resection. Clinical trial information: NCT02632409 . [Table: see text]